PROJECT SUMMARY/ABSTRACT It is estimated that nearly 1.5 million bone grafting procedures are performed annually in the U.S., and this number is expected to rise as our population ages. Human mesenchymal stem cell (hMSC) based bone tissue engineering has long been heralded as a promising solution to this problem and the limitations of bone autografts, but preclinical and clinical trials with hMSCs have not met expectations. Thus, the goal of this project is to develop an osteoinductive hydrogel-based scaffold that can deliver hMSCs and improve their therapeutic efficacy for bone repair. The approach for this project is based on using tunable poly(ethylene glycol)-based hydrogel microspheres as building blocks for cell-instructive scaffolds. Subsequently, in vivo testing will be performed to test whether these cell-instructive biomaterials can induce a therapeutically significant effect on bone defect healing. This project has two specific aims: (Aim 1) Microgel scaffolds, which will be assembled with click chemistry, will be engineered to induce hMSC osteogenesis by engaging cells through ?5?1 integrins and by mechanotransduction. (Aim 2) Osteoinductive microgel-based scaffolds will be combined with hMSCs and then tested in a nude mouse femoral defect model. Bone healing will be evaluated by CT and histology and compared to a clinical benchmark to determine the relative efficacy of the scaffolds and hMSCs. Research team and environment: This project spans the Department of Biomedical Engineering at Texas A&M University and the Institute for Regenerative Medicine in the Texas A&M Health Science Center. It will be led by Dr. Daniel Alge (PI) and Dr. Carl Gregory (Co-I). Dr. Alge is an assistant professor in the Department of Biomedical Engineering with expertise in developing hydrogel biomaterials for cell delivery. Dr. Gregory is an associate professor in the Institute for Regenerative Medicine with expertise in hMSCs and bone tissue engineering.